Shared Mechanisms Allow SARS-CoV-2 Variants to Thrive Post-Vaccination

Scientists at UCSF QBI, University College London and the Icahn School of Medicine at Mount Sinai reported breakthrough findings in a study published Sept. 21, 2023, on convergent evolutionary mechanisms shared by COVID-19 variants, allowing them to overcome both adaptive and innate immune system barriers.

In the paper titled, SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response, scientists carried out an unprecedented, systematic comparative study using the most infectious COVID-19 variants, namely Alpha, Beta, Gamma, Delta and Omicron to identify specific viral mutations responsible for hijacking a common host pathway, thereby leading to increased transmissibility, infectivity and survival. Specifically, they discovered a convergence in potent suppression of interferon-stimulated genes through several viral proteins, including Orf6 and Orf9b, which serve as innate immune antagonist proteins capable of blocking innate host immune response.

The study, led by the laboratories of Nevan Krogan, Ph.D., Director of the Quantitative Biosciences Institute (QBI) at the School of Pharmacy at UC San Francisco, Senior Investigator at Gladstone Institutes, was a collaborative effort that involved 16 institutions in six countries, including University College London (UCL) in London, England (Greg Towers and Clare Jolly) and Icahn Mount Sinai (Adolfo Garcia-Sastre and Lisa Miorin) among others.

Krogan also received special recognition as the recipient of the first-ever “Discovery | Innovation | Health Prize” from Research!America for his “trailblazing efforts to address future pandemic threats” and acknowledgement of his approach to building global collaborations in advance of future health threats as a preemptive strategy to protect human life, health, and opportunity. The award, which included a $200,000 prize, is intended to provide support for his vision for progress against pandemic threats.

“Unfortunately, we continue to see new mutations and strains of SARS-CoV-2 despite innovations in new vaccines,” said Krogan, who founded the QBI Coronavirus Research Group (QCRG). “We evaluated each of the viral variants in isolation and discovered that there was a common mechanism involving several viral proteins, including Orf6 and Orf9b, that potently suppresses innate immunity. This finding is consistent with our investigation of early SARS-CoV-2 variants where certain viral proteins were highly expressed in infected cells which helped the virus infect our cells. With our additional research across SARS-CoV-2 variants, we now see this as a crucial finding that, if targeted effectively, could be turned into a significant vulnerability for this virus, which also has important implications for management of future pandemics.”

In a second paper titled “Impact of SARS-CoV-2 Orf6 and its variant polymorphisms on host responses and viral pathogenesis” also published today in Cell Host & Microbe, the researchers further detailed the role of Orf6 in subverting important pathways involved in the host antiviral response.

“In this study we found that Orf6 is a major SARS-CoV-2 innate immune antagonist by selectively interfering with nucleocytoplasmic trafficking through direct interactions with the nuclear pore complex”, said Lisa Miorin, PhD, assistant professor of microbiology at Mount Sinai. “We show that the absence of ORF6, or the introduction of ORF6 loss-of-function mutations, significantly influences the host antiviral responses resulting in SARS-CoV-2 attenuation in animal models.”

Adolfo García-Sastre, PhD, professor of medicine (Infectious Diseases), microbiology and pathology, molecular and cell based medicine and Director of the Global Health and Emerging Pathogens Institute at Mount Sinai added, “These observations provide a potential new way to address viral pandemics by targeting a common pathway that the virus uses for infectivity, a different approach from vaccines that are created to target mutated Spike proteins within individual variants. By investigating the variant’s ability to suppress the host immune response we have uncovered what appears to be a mechanism that viruses use that can be exploited.”

Mehdi Bouhaddou, PhD, assistant professor Department of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles (UCLA) who contributed to the research during his prior post-doctoral fellowship at UCSF commented, “We believe the future approach to managing pandemics will require a drug combination cocktail, similar to treatment regimens for HIV, that will include vaccines and antiviral innovations to target the virus. Specifically, combination therapy approaches to target the adaptive immune response (e.g., vaccines, antibody treatments) and another inhibiting viral innate immune antagonist proteins (e.g., Orf6 and Orf9b) or activating the innate immune response, could be the most effective.  Perhaps with this approach, we may be able to get ahead of viruses before they reach pandemic levels.”

To understand the effect of viral mutations on viral replication and cellular responses, the researchers systematically studied the five SARS-CoV-2 variants of concern during infection in human airway epithelial cells. Their analysis pinpointed cellular pathways that are similarly modulated across variants during infection and represent putative targets for pan-coronavirus antivirals. They observed most of the variants improve their ability to inhibit the host innate immune response, which likely contributed to variant dominance by improving transmission. They reason this reflects a strong selection imposed by the human innate immune system on the virus, whose ancestor likely adapted to evade innate immunity in a non-human species. The researchers concluded that a major force in shaping SARS-CoV-2 virus-host adaptations is related to evasion of innate and adaptive responses, a finding that has also been shown in research evasion of innate immune responses in HIV.

About QBI: The Quantitative Biosciences Institute (QBI) is a University of California organized research unit reporting through the UCSF School of Pharmacy. QBI fosters collaborations across the biomedical and the physical sciences, seeking quantitative methods to address pressing problems in biology and biomedicine. Motivated by problems of human disease, QBI is committed to investigating fundamental biological mechanisms, because ultimately solutions to many diseases have been revealed by unexpected discoveries in the basic sciences. Learn more at

About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. Learn more at or see our Fact Sheet.

Authorship and funding: This work was funded by grants from the National Institute of Mental Health and the National Institute of Allergy and Infectious Diseases, both part of the National Institutes of Health; the Defense Advanced Research Projects Agency; the Center for Research for Influenza Pathogenesis; the Centers of Excellence for Influenza Research and Surveillance of the National Institute of Allergy and Infectious Diseases; the Centers of Excellence for Integrative Biology of Emerging Infectious Diseases of the Agence Nationale de la Recherche (France); F. Hoffmann-LaRoche AG; Vir Biotechnology, Centre for Integrative Biological Signalling Studies (CIBSS), European Research Council (ERC) and QCRG philanthropic donors. Shokat is a Howard Hughes Medical Institute investigator.